Prophylactic or therapeutic drug for renal diseases

ABSTRACT

This invention relates to methods for lowering urinary total protein comprising, administering as an active ingredient, a compound or salt thereof represented by general formula (I)                    
     wherein R 1  stands for H or alkyl; R 2  stands for an optionally esterified carboxyl group; R 3  stands for a group actually or potentially capable of forming an anion; X shows that the phenylene and phenyl groups bind to each other directly or through a spacer having an atomic chain length of two or less; n stands for 1 or 2; ring A stands for a benzene ring having an optional substituent in addition to R 2 ; Y stands for a bond, —O—, —S(O)m— wherein m stands for 0, 1 or 2, or —N(R 4 )— wherein R 4  stands for H or an optionally substituted alkyl group.

This application is a divisional application of Ser. No. 09/467,488,filed Dec. 20, 1999, now U.S. Pat. No. 6,319,938 which a divisional ofSer. No. 09/207,043 filed Dec. 8, 1998, now U.S. Pat. No. 6,040,324which is a continuation of Ser. No. 08/965,416 filed Nov. 6, 1997, nowU.S. Pat. No. 5,889,036 which is a divisional of Ser. No. 08/696,475filed Aug. 14, 1996, now U.S. Pat. No. 5,719,173 which is a divisionalof Ser. No. 08/229,930 filed Apr. 19, 1994, now abandoned, which claimspriority of Japanese Patent No. 095942-1993, filed Apr. 22, 1993.

FIELD OF THE INVENTION

This invention relates to a prophylactic or therapeutic drug containingan angiotensin II antagonistic compound or salt thereof as the activeconstituent, for diabetic nephropathy or glomerulonephritis.

BACKGROUND OF THE INVENTION

The kidneys are a major target organ of hypertension. Prolongedhypertension induces various renal impairments, mainly throughrenovascular lesions. Among them, contraction of renal vessels anddegenerative lesions of elastic fibers lead to further elevation of theblood pressure. It is generally believed that hypertension raises renalintraglomerular pressure, which overloads the glomeruli, stimulatingfibrosis and enlargement of the mesangial region, which advances tohardening of the glomeruli. In diabetic nephropathy as well, elevationin intraglomerular pressure is followed by trace albuminuria,progressing to the sclerosis of the glomeruli. Eventually, renalfunctions decline, resulting in chronic renal failure requiringartificial dialysis therapy. In recent years, 20% of patients withend-stage renal failure who commence artificial dialysis have diabeticnephropathy as the underlying disease. The number of patients likely toreceive artificial dialysis tends to increase year after year, posing acritical problem in the medical care system. At present, it is said thatthere are few ideal pharmaceutical therapies for chronic renal failure,and even that blood-pressure-lowering therapy may aggravate rather thanimprove renal failure.

Angiotensin II antagonistic compounds are known as a therapeutic drugfor cardiovascular diseases, e.g., hypertension, cardiac diseases (heartenlargement, heart failure, myocardial infarction, etc.), apoplexy,nephritis, etc. (European Patent Official Gazette (EPO) 459136A). Themechanism of their action is considered to be based on inhibition ofbinding to the angiotensin II receptor of angiotensin II, whichpossesses intense vasoconstrictive action. EP 459136A₁ describes theavailability of angiotensin II antagonists in the treatment ofnephropathy or nephritis.

Many data of clinical and experimental studies have been reported on therelation between renal diseases and hypertension. It is now establishedhat the kidneys are directly or indirectly involved in the onset ofhypertension, and also are apt to be affected by hypertension. However,hypertension in chronic glomerulonephritis has been poorly elucidated,particularly as to causative factors, effects of hypertension on thecourse of nephritis, and prophylactic effects of blood pressure loweringtherapy.

Currently, nephritis is considered to be a clinical picture of differentdiseases with different entities. In accordance with the popularizationof renal biopsy, renal diseases have been reviewed, resulting in theirredefinition as a wide range of diseases characterized by proteinuria(“Shibata's Internal Medicine of the Kidneys,” by Seiichi Shibata,Bunkodo, 1988). Glomerulonephritis, once regarded as a single disease,has been differentiated into glomerulonephritis, chronic pyelonephritis,IgA nephropathy, periarteritis nodosa, gout, diabetes, systemic lupuserythematosus (SLE), hepatic infarction, hereditary renal disease,amyloidosis, and Wegener's sarcoma.

Diabetes associated with hypertension facilitates cardiovascularimpairment and/or other organ complications, greatly affecting lifeexpectancy. Accordingly, it is important to control blood pressurewithin the normal range during treatment, along with the control ofdiabetes and the improvement or prevention of arteriosclerosis.

OBJECT OF THE INVENTION

This invention provides a prophylactic or therapeutic drug for diabeticnephropathy or glomerular nephritis.

SUMMARY OF THE INVENTION

Under the above-mentioned circumstances, the inventors intensivelystudied to develop a drug for the prophylaxis or treatment ofnephropathy or nephritis. Ultimately, they found that compoundspossessing angiotensin II antagonistic action, represented by aparticular structural formula, are very effective in the prophylaxis ortreatment of diabetic nephropathy or glomerulonephritis. The presentinvention was thus accomplished.

Namely, this invention relates to a prophylactic or therapeutic drug fordiabetic nephropathy or glomerulonephritis, containing, as the activeconstituent, a compound or salt thereof represented by formula (I):

(wherein R¹ stands for H or an optionally substituted hydrocarbonresidue; R² stands for an optionally esterified carboxyl group; R³stands for a group actually or potentially capable of forming an anion;X shows that the phenylene and phenyl groups bind to each other directlyor through a spacer having an atomic chain length of two or less; nstands for 1 or 2; ring A stands for a benzene ring having one or twooptional substituents in addition to R²; Y stands for a bond, —O—,—S(O)_(m)— (wherein m stands for 0, 1 or 2), or —N(R⁴)— (wherein R⁴stands for H or an optionally substituted alkyl group)).

DETAILED DESCRIPTION OF THE INVENTION

The invented compounds used for prophylactic or therapeutic purposes, asrepresented by formula (I), are structurally very prominentlycharacterized by the coexistence of R², standing for an optionallyesterified carbozyl group, and R³, standing for a group actually orpotentially capable of forming an anion. This structural characteristiccontributes to the onset of very intense prophylactic or therapeuticeffect on diabetic nephropathy or glomerulonephritis.

The compounds of this invention, possessing angiotensin II antagonisticaction, represented by formula (I), can be favorably used in theprophylaxis or treatment of diabetic nephropathy or glomerulonephritis.

In formula (I), R¹ stands for H or an optionally substituted hydrocarbonresidue.

Examples of the hydrocarbon residue represented by R¹ include alkyl,alkenyl, alkynyl, cycloalkyl, aryl and aralkyl groups. Among them alkyl,alkenyl and cycloalkyl groups are preferable.

The alkyl group represented by R¹ is a straight chain or branched loweralkyl group having 1 to about 8 carbon atoms, as exemplified by methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,i-pentyl, hexyl, heptyl or octyl.

The alkenyl group represented by R¹ is a straight chain or branchedlower alkenyl group having 2 to about 8 carbon atoms, as exemplifed byvinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl or 2-octenyl.

The alkynyl group represented by R¹ is a straight chain or branchedlower alkynyl group having 2 to about 8 carbon atoms, as exemplified byethynyl, 2-propinyl, 2-butynyl, 2-pentynyl or 2-octyl.

The cycloalkyl group represented by R¹ is a lower cycloalkyl grouphaving 3 to about 6 carbon atoms, as exemplified by cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

The above mentioned alkyl, alkenyl, alkynyl or cycloalkyl group mayoptionally be substituted with hydroxyl group, an optionally substitutedamino group (e.g. amino, N-lower (C₁₋₄) alkylamino or N,N-dilower (C₁₋₄)alkylamino), halogen, a lower (C₁₋₄) alkoxy group, a lower (C₁₋₄)alkylthio group.

The aralkyl group represented by R¹ is, for example, a phenyl-lower(C₁₋₄) alkyl such as benzyl or phenethyl, and the aryl group representedby R₁ is, for example, phenyl.

The above mentioned aralkyl or aryl group may optionally have, on anyposition of its benzene ring, for example, halogen (e.g. F, Cl or Br),nitro, an optionally substituted amino group (e.g. amino, N-lower (C₁₋₄)alkylamino or N,N-dilower (C₁₋₄) alkylamino), lower (C₁₋₄) alkoxy (e.g.methoxy or ethoxy), lower (C₁₋₄) alkylthio (e.g. methylthio orethylthio) or lower (C₁₋₄) alkyl (e.g. methyl or ethyl).

Among the above mentioned groups represented by R¹, optionallysubstituted alkyl, alkenyl or cycloalkyl groups (e.g. a lower (C₁₋₅)alkyl, lower (C₂₋₅) alkenyl or lower (C₃₋₆) cycloalkyl group optionallysubstituted with hydroxyl group, amino group, halogen or a lower (C₁₋₄)alkoxy group) are preferable.

Y stands for a bond, —O—, —S(O)_(m)— (wherein m is 0, 1 or 2) or —N(R⁴)—(wherein R⁴ is hydrogen or an optionally substituted lower alkyl group).Y is preferably a bond, —O—, —S— or —N(R⁴)— (wherein R⁴ is hydrogen or alower (C₁₋₄) alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, t-butyl)).

With respect to formula (I) above, the group for R³, capable of formingan anion ( a group having a hydrogen atom capable of leaving as aproton), or a group capable of changing thereto, is exemplified by 5- to7- membered (preferably 5- or 6- membered) monocyclic heterocyclic ringresidues which contain one or more of N, S and O and which may besubstituted (preferably N-containing heterocyclic residues having ahydrogen atom capable of leaving as a proton), and groups capable ofchanging thereto in vivo. Such groups include the following:

The chemical bond between the group for R³ and the partner phenyl groupmay be a carbon-carbon bond as shown above, or a nitrogen-carbon bondvia one of the several nitrogen atoms when the symbol g stands for —NH—in the above formulas. For instance,

when R³ is represented by

embodiments are

Other R³ examples binding through the nitrogen atom are

In the above groups, g stands for —CH₂—, —NR⁷—, oxygen atom, or

each stand for a carbonyl group, a thiocarbonyl group or an optionallyoxidized sulfur atom (e.g., S, S(O), S(O)₂) (preferably, a carbonyl orthiocarbonyl group; more preferably, a carbonyl group); m stands for theinteger 0, 1 or 2; R⁷ stands for a hydrogen atom or an optionallysubstituted lower alkyl group (e.g. a lower (C₁₋₄) alkyl group (e.g.methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl)).

Preferable examples of R³ include 2,5-diydro-5-oxo-1,2,4-oxadiazole ringresidue, 2,5-dihydro-5-thioxo-1,2,4-oxadiazole ring residue or2,5-dihydro-5-oxo-1,2,4-thiadiazole ring residue having —NH or —OH groupas proton donor and carbonyl group, thiocarbonyl group or sulfinyl groupas proton acceptor simulateneously.

And, while the heterocyclic residue represented by R³ may form acondensed ring by connecting the substituents on the ring, it ispreferably a 5- to 6-membered ring, more preferably a 5-memberedheterocyclic residue. Especially groups represented by the formula

wherein i stands for —O— or —S—; j stands for >C═O, >C═S or >S(O)_(m); mstands for the integer 0, 1 or 2 (in particular,2,5-dihydro-5-oxo-1,2,4-ozadiazole-3-yl;2,5-dihydro-5-thioxo-1,2,4-ozadiazole-3-yl;2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) are preferable. R³ can besubstituted at the ortho, meta or para position, most preferably at theortho position.

In addition, the above-mentioned heterocyclic residue (R³) have thefollowing tautomeric isomers:

when Z=0, and g=0

the three tautomeric isomers a, b and c exist.

The heterocyclic residue represented by the above formula comprises allof these a, b and c.

Moreover, R³ may be a carboxyl group, tetrazolyl group,trifluoromethanesulfonamide group (—NHSO₂CF₃), phosphate group, sulfonicgroup, cyano group, or lower (C₁₋₄) alkoxycarbonyl group; these groupseach may be protected by an optionally substituted lower alkyl oracylgroup. Any group capable of forming an anion biologically orphysiologically (e.g. through biological reactions such as oxidation,reduction or hydrolysis caused by enzymes in the body) or chemically, ora group capable of changing thereto is acceptable.

As R³, a tetrazolyl or carboxyl (preferably tetrazolyl) group optionallyprotected by an optionally substituted lower (C₁₋₄) alkyl (e.g., methyl,triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl,p-nitrobenzyl, etc.) or acyl (e.g., lower (C₂₋₅) alkanoyl, benzoyl,etc.) group is preferable. R³ can be replaced at the ortho, meta or paraposition, most preferably at the ortho position.

X stands for a covalent bond between the 2 phenyl rings or a spacerhaving a chain length of 1 to 2 atoms as the linear moiety between theadjoining phenylene group and phenyl group. Preferably, X is a covalentbond. The spacer having a chain length of 1 to 2 atoms may consist of adivalent chain in which the number of atoms composing the straight chainportion is either 1 or 2, and may have a side chain. For example, alower (C₁₋₄) alkylene, —CO—, —O—, —S—, —NH—, —CO—NH—, —O—CH₂—, —S—CH₂—,—CH═CH—, etc. are listed.

n stands for the integer 1 or 2 (preferably 1).

The formula represented by the above-mentioned R³, X and n:

is preferably represented by the formula:

R² in formula (I) is an optionally esterified carboxyl group.

The optionally esterified carboxyl group as R² includes the grouprepresented by the formula —CO—D [wherein D stands for a hydroxyl groupor an optionally substituted alkoxyl group {e.g., a lower (C₁₋₆) alkoxylgroup whose alkyl portion is optionally substituted with a hydroxyl,optionally substituted amino (e.g., amino, dimethylamino, diethylamino,piperidino, molphorino, etc.), halogen, lower (C₁₋₆) alkoxyl, lower(C₁₋₆) alkylthio or optionally substituted dioxolanyl (e.g.,5-methyl-2-oxo-1,3-dioxolane-4yl, etc.) group, or the group representedby the formula —O—CH(R⁶)—OCOR⁵ [wherein R⁶ stands for H, a lower (C₁₋₆)straight chain or branched alkyl group (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl neopentyl,etc.), a lower (C₂₋₆) straight chain or branched alkenyl group or alower (C₃₋₈) cycloalkyl group (e.g., cyclopentyl, cyclohexyl,cycloheptyl, etc.); R⁵ stands for a lower (C₁₋₆) straight chain orbranched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), alower (C₂₋₆) straight chain or branched alkenyl group, a lower (C₃₋₈)cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.), alower (C₁₋₃) alkyl group substituted with C₃₋₈ cycloalkyl (e.g.cyclopentyl, cyclohexyl, cycloheptyl) or an optionally substituted arylgroup such as phenyl group (e.g., benzyl, p-chlorobenzyl, phenetyl,cyclopentylmethyl, cyclohexylmethyl, etc.), a lower (C₂₋₃) alkenyl groupoptionally substituted with C₃₋₈ cycloalkyl or an optionally substitutedaryl group such as phenyl (e.g., cinnamyl, etc. having alkenyl moietysuch as vinyl, propenyl, allyl and isopropenyl, etc.), an aryl groupsuch as optionally substituted phenyl (e.g., phenyl, p-tolyl, naphtyl,etc.), a lower (C₁₋₆) straight chain or branched alkoxyl group (e.g.;methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl,sec-butoxyl, t-butoxyl, n-pentyloxyl, isopentyloxyl, neopentyloxyl,etc.), a lower (C₂₋₈) straight chain or branched alkenyloxyl group(e.g., allyloxyl, isobutenyloxyl, etc.), a lower (C₃₋₈) cycloalkyloxylgroup (e.g., cyclopentyloxyl, cyclohexyloxyl, cycloheptyloxyl, etc.), alower (C₁₋₃) alkoxyl group substituted with a C₃₋₈ cycloalkyl (e.g.,cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an aryl group such asoptionally substituted phenyl (e.g., benzyloxy, phenethyloxy,cyclopentylmethyloxy and cyclohexylmethyloxy having alkoxy moiety suchas methoxy, ethoxy, n-propoxy and isopropoxy), a lower (C₂₋₃) loweralkenyloxy group substituted with a C₃₋₈ cycloalkyl (e.g., cyclopentyl,cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl groupsuch as phenyl group (e.g., cinnamyloxy etc. having alkenyloxy moietysuch as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.), or anoptionally substituted aryloxyl group such as phenoxyl (e.g., phenoxyl,p-nitrophenoxyl, naphtoxyl, etc.,)}]. The substituent for R² may be agroup actually or potentially capable of forming an anion [e.g.,tetrazolyl group, trifluoromethanesulfonamide group, phosphate group orsulfonic group optionally protected by an alkyl {e.g., lower (C₁₋₄)alkyl, etc.} or acyl {e.g., lower (C₂₋₅) alkanoyl, optionallysubstituted benzoyl, etc:} group].

For example, the following substituents are listed: —COOH and its salts,—COOMe, —COOEt, —COOtBu, —COOPr, pivaloyloxymethoxycarbonyl,1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl,(5-methyl-2-oxo-1,3-dioxolane4-yl)methoxycarbonyl,acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl,n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl,1-(ethoxycarbonyloxy)ethoxycarbonyl, 1-(acetoxy)ethoxycarbonyl,1-(isobutylyloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl,benzoyloxymethoxycarbonyl, cinnamiloxycarbonyl andcyclopentylcarbonyloxymethoxycarbonyl, etc. Furthermore, R² may be anyof the groups actually or potentially capable of forming an anion (e.g.,COO³¹ or its derivatives, etc.) under biologic, or physiologic,conditions (e.g., oxidation or reduction induced by an enzyme present inthe living body; in vivo reaction such as hydrolysis) or chemically. R²may also be a carboxyl group or its prodrug. R² may be a group capableof being biologically or chemically biotransformed to an anion.

Among the groups described as R², preferable ones include carboxyl,esterified carboxyl (e.g. methyl ester, ethyl ester or an ester formedby binding of a group represented by the above mentioned formula—O—CH(R⁶)—OCOR⁵ to carbonyl) and optionally protected tetrazolyl,carboaldehyde and hydroxymethyl.

In general formula (I), ring A may have, in addition to the grouprepresented by R², another substituent, e.g., a halogen atom (e.g., F,Cl, Br, etc.), cyano group, nitro group, lower (C₁₋₄) alkyl group, lower(C₁₋₄) alkoxyl group, optionally substituted amino group {e.g., amino,N-lower (C₁₋₄) alkylamino (e.g., methylamino, etc.), N,N-dilower (C₁₋₄)alkylamino (e.g., dimethylamino, etc.), N-arylamino (e.g., phenylamino,etc.), alicyclic amino (e.g., morpholino, piperidino, piperazino,N-phenylpiperazino, etc.), etc.}, a group represented by the formula—CO—D′ [wherein D′ stands for a hydroxyl group or a lower (C₁₋₄) alkoxylgroup whose alkyl moiety may be substituted with a hydroxyl group, lower(C₁₋₄) alkoxyl group, lower (C₂₋₆) alkanoyloxy (e.g., acetoxyl,pivaloyloxyl, etc.) or lower (C₁₋₆) alkoxycarbonyloxyl (e.g.,methoxycarbonyloxyl, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.)group], or tetrazolyl, trifluoromethanesulfonamide, phosphoric acid orsulfonic acid group which may be protected by lower (C₁₋₄) alkyl or acylgroup (e.g., lower (C₂₋₅) alkanoyl, optionally substituted benzoyl,etc.); among them, a lower (C₁₋₄) alkyl group and a halogen group arepreferable. Of these substituents, one or two may simultaneouslysubstitute for groups at available positions in the ring.

Among the compounds represented by the above mentioned formula (I),compounds represented by formula (r) are preferred:

[wherein ring A stands for a benzene ring which may have another 1 or 2substituents in addition to the group represented by R²; R¹ stands for Hor an optionally substituted lower (C₁₋₆) alkyl (preferably lower (C₁₋₄)alkyl); Y stands for O, N(H) or S; R² is a group represented by theformula —CO—D″ [wherein D″ stands for hydroxyl group, or a lower (C₁₋₄)alkoxy whose alkyl moiety is optionally substituted with hydroxyl group,amino, halogen, a lower (C₂₋₆) alkanoyloxy (e.g. acetyloxy andpivaloyloxy, etc.), lower (C₄₋₇) cycloalkanoyloxy, lower (C₁₋₆)alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy), lower(C₃₋₇) cycloalkoxycarbonyloxy (e.g. cyclohexyloxycarbonyloxy) or a lower(C₁₋₄) alkoxy; R³ stands for a tetrazolyl, carboxyl group or groupsrepresented by the formula,

wherein i stands for —O— or —S—; j stands for >C═O, >C═S or >S(O)_(m);and m is of the same meaning as defined above, which are optionallyprotected with optionally substituted lower (C₁₋₄) alkyl (e.g. methyl,triphenylmethyl, methoxymethyl, acetyloxymethyl,methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,1-(cyclohexyloxycarbonyloxy)ethyl and pivaloyloxymethyl, etc.) or anacyl group (e.g. a lower C₂₋₅ alkanoyl and benzoyl, etc.).; n is 1 or 2.

In the formula (I′), substituents on the optionally substituted loweralkyl for R¹ include a hydroxyl group, an amino group, halogen and alower (C₁₋₄) alkoxy group.

In the formula (I′), ring A is a benzene ring which may have asubstituent, in addition to the group R², such as a halogen (e.g., F,Cl, Br), lower (C₁₋₄) alkyl, lower (C₁₋₄) alkoxy, nitro, a grouprepresented by the formula —CO—D′, wherein D′ represents a hydroxylgroup or a lower (C₁₋₄) alkoxy whose alkyl moiety may be substitutedwith a hydroxyl group, lower (C₁₋₄) alkoxy, lower (C₂₋₆) alkanoyloxy(e.g., acetoxy, pivaloyloxy, etc.) or lower (C₁₋₆) alkoxycarbonyloxy(e.g., methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy),or an amino which may be substituted with a lower (C₁₋₄) alkyl(preferably a substituent such as a lower (C₁₋₄) alkyl or halogen). Morepreferably, A is a benzene ring which has no substituent in addition tothe group represented by the formula R².

As the salt thereof, pharmaceutically acceptable salts are used, e.g., asalt with an inorganic base, organic base, inorganic acid, organic acid,or basic or acidic amino acid. Inorganic bases appropriate to form thesalt include alkali metals such as sodium and potassium, alkali soilmetals such as calcium and magnesium, aluminum and ammonium. Organicbases appropriate to form the salt include trimethylamine,triethylamine, pyridine, picoline, ethanolamine, jetanolamine,triethanolamine, dicyclohexylamine, and N,N′-dibenzylethylenediamine.Inorganic acids appropriate to form the salt include hydrochloric acid,hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.Organic acids appropriate to form the salt include formic acid, aceticacid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, malic acid, methanesulfonicacid, benzenesulfonic acid, and p-toluenesulfonic acid. Basic aminoacids to form the salt include arginine, lysine and ornithine. Acidicamino acids to form the salt include aspartic acid and glutamic acid.

As an active ingredient of the present invention, the compoundsdescribed in the Examples of Japan Provisional Publication No.364171/1992 and EP520423 are preferred.

The compounds represented by general formula (I) were, for instance,disclosed in Provisional Publication Nos. 9373/1992 and 364171/1992, andEP520423, and can be manufactured as described in these publications.

Compound (I) or salts thereof possessing angiotensin II antagonisticaction referred to in the present invention are of sufficiently lowtoxicity to be used as a pharmaceutical for animals, particularlymammals (e.g., humans, dogs, rabbits, rats, mice, etc.), in theprophylaxis or treatment of diabetic nephropathy or glomerulonephritis.

Compound (I) or salts thereof represented by general formula (I) can beadministered by the oral route, non-oral route, inhalation, rectalinjection, or topical administration, as pharmaceutical constituents orpreparations (e.g., powder, granules, tablets, pills, capsules,injection, syrup, emulsion, elixir, suspension, solution, etc.). Atleast one compound of the present invention can be used singly or inmixture with a carrier allowable as a pharmaceutical (adjuvant, vehicle,supportive agent, and/or diluting agent).

The constituents of a pharmaceutical can be prepared according to theusual manner. In the present specification, the non-oral route includessubcutaneous injection, intravenous injection, intramuscular injection,peritoneal injection and intravenous drip. For prescription injection,sterile aqueous or oily suspensions for injection can be prepared byusing an appropriate emulsifier or humidifier and a suspending agent,according to known methods. The sterile prescription agent for injectionmay be a non-toxic, non-orally administrable diluting agent such asaqueous solution or a sterile injectable solution or suspension in asolvent. As the usable vehicle or solvent, water, Ringer's solution,isotonic saline, etc. are allowed; as an ordinary solvent, or suspendingsolvent, sterile involatile oil can be used. For these purposes, anykind of involatile oil and fatty acid can be used, including natural orsynthetic or semisynthetic fatty oils or fatty acids; natural orsynthetic or semisynthtetic mono- or di- or tri-glycerides.

The suppository for rectal administration can be manufactured via aparticular process, in which the drug is mixed with an appropriate,non-irritant supporting agent, e.g., cocoa butter or polyethyleneglycol, that is solid at normal temperature but liquid at intestinaltemperature and therefore melts in the rectum to release the drug.

As the solid-type dosage form for oral administration, powder, granules,tablets, pills and capsules are listed as mentioned above. In thesedosage forms, the active constituent compound can be mixed with at leastone additive, including sucrose, lactose, cellulose, mannitol, maltitol,dextran, starches, agar, arginates, chitins, chitosans, pectins, gumtragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic orsemisynthetic polymer, and glyceride. These dosage forms can alsocontain other type(s) of additives, e.g., inactive diluting agent,lubricant such as magnesium stearate, paraben, preserving agent such assorbic acid, ascorbic acid, a-tocopherol, antioxidant such as cysteine,disintegrator, binder, thickener, buffering agent, sweetening agent,flavoring agent, perfuming agent, etc. Tablets and pills can be furtherprocessed into enteric coated preparations. The liquid preparations fororal administration include emulsion, syrup, elixir, suspension andsolution preparations allowable for medical use. These preparations maycontain inactive diluting agents ordinarily used in said field, e.g.,water.

The dosage for a particular patient is determined according to age, bodyweight, general health conditions, sex, diet, administration time,administration method, excretion rate, drug combination, and severity ofthe illness being treated, in consideration of those or other factors.

The compounds and salts thereof represented by general formula (I) canbe safely used at low toxicity level; the daily dose varies with patientcondition, body weight, type of compound, administration route, etc.;e.g., non-orally, i.e. for subcutaneous, intravenous, intramuscular orintrarectal use, approximately 0.01-50 mg/person/day, preferably 0.01-20mg/person/day, and orally, approximately 0.01-150 mg/person/day,preferably 0.1-100 mg/person/day, are recommended.

The invention is described in more detail with reference to examples.However, the invention is not limited to the specific embodiments.

EXAMPLE Preparation Example

The prophylactic or therapeutic drug containing compound (I) or a saltthereof, referred to in the present invention as the active constituentfor diabetic nephropathy or glomerular nephritis, for instance, can bemanufactured according to the following formula:

1. Capsules

(1) 2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]- 10 mg1H-benzimidazole-7-carboxylic acid (2) Lactose 90 mg (3)Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg Onecapsule 180 mg

After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a agelatin capsule.

2. Tablets

(1) 2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]- 10 mg1H-benzimidazole-7-carboxylic acid (2) Lactose 35 mg (3) Corn starch 150mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg Onetablet 230 mg

After (1) is mixed with (2), (3), ⅔ of (4) and half of (5), the mixtureis granulated. To the granules, the remaining amounts of (4) and (5) areadded; the mixture is then press-shaped into a tablet.

3. Injection

(1) 2-methylthio-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4- 10 mgyl]methyl]-1H-benzimidazole-7-carboxylic acid disodium salt (2) Inositol100 mg (3) Benzylalcohol 20 mg One ampule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to makethe total volume 2 ml; the solution is sealed in an ampule. The entireprocess should be conducted under sterile conditions.

4. Capsules

(1) (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′- 10 mg(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate(2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesiumstearate 10 mg One capsule 180 mg

After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

5. Tablets

(1) (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′- 10 mg(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate(2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose30 mg (5) Magnesium stearate 5 mg One tablet 230 mg

After (1) is mixed with (2), (3), ⅔ of (4), and half of (5), the mixtureis granulated. To the granules, the remaining amounts of (4) and (5) areadded; the entire mixture is then press-shaped into a tablet.

6. Injection

(1) 2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]- 10 mg1H-benzimidazole-7-carboxylic acid disodium salt (2) Inositol 100 mg (3)Benzylalcohol 20 mg One ampule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to makethe total volume 2 ml; the solution is then sealed in an ampule. Theentire process should be conducted under sterile conditions.

7. Capsules

(1) 2-butyl-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]- 10 mg1H-benzimidazole-7-carboxylic acid (2) Lactose 90 mg (3)Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg Onecapsule 180 mg

After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

8. Tablets

(1) 2-butyl-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]- 10 mg1H-benzimidazole-7-carboxylic acid (2) Lactose 35 mg (3) Corn starch 150mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg Onetablet 230 mg

After (1) is mixed with (2), (3), ⅔ of (4) and half of (5), the mixtureis granulated. To the granules, the remaining amounts of (4) and (5) areadded; the mixture is then press-shaped into a tablet.

9. Capsules

(1) Pivaloyloxymethyl 2-butyl-1-[[2′-(1H-tetrazole-5- 10 mgyl)biphenyl-4-yl]methyl]-1H-benzimidazole-7- carboxylate (2) Lactose 90mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg Onecapsule 180 mg

After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

10. Tablets

(1) Pivaloyloxymethyl 2-ethoxy-1-[[2′-(1H-tetrazole-5- 10 mgyl)biphenyl-4-yl]methyl]-1H-benzimidazole-7- carboxylate (2) Lactose 35mg (3) Corn starch 150 mg (3) Microcrystalline cellulose 30 mg (4)Magnesium stearate 5 mg Total 230 mg per tablet

Components (1), (2), (3), a two-thirds portion of component (4) and ahalf portion of component (5) were mixed and granulated. To thesegranules, the remaining portions of components (4) and (5) were added,and the whole mixture tableted by compressive tableting.

11. Capsules

(1) 2-ethoxy-1-[[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3- 10 mgyl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (2) Lactose90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mgOne capsule 180 mg

After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

12. Tablets

(1) 2-ethoxy-1-[[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3- 10 mgyl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (2) Lactose35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5)Magnesium stearate 5 mg One tablet 230 mg

After (1) is mixed with (2), (3), ⅔ of (4) and half of (5), the mixtureis granulated. To the granules, the remaining amounts of (4) and (5) areadded; the mixture is then press-shaped into a tablet.

The biologic activity of compounds and salts thereof possessingangiotensin-II-antagonistic action are described in Test Examples.

Test Example 1

Antiproteinuric action in rats with subtotally (5/6) nephrectomy (focalglomerulorsclerosis model; Meyer, T. W. and Renake, H. G.: Am. J.Physiol. 254, F856 (1988) or Yoshioka, T., Shiraga, H., Yoshida, Y.,Fogo. A., Glick, A. D.: J. Clin. Invest. 82, 1614 (1988)) Compound 1:(±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzmidazole-7-carboxylateMethod: Five-week-old male rats were anesthetized by intraperitonealinjection of pentobarbital sodium and ⅔ of the right kidney was removed.One week later, the entire left kidney was removed under similaranesthesia. After two-week breeding, 24-hour urine was collected and thetotal protein content and albumin content in the urine were determinedby the use of A/G-B test (Wako Pure Chemistry Co., Ltd.). On the basisof urinary protein and blood pressure (BP), the rats were divided intotwo groups (vehicle-treated rats and rats treated with 1 mg/kg/day, p.o.of compound 1). Rats undergoing nephrectomy of the left kidney alonewere also used as sham operated rats. Compound 1 was suspended ingum-arabic and the suspension was orally administered once a day foreight weeks. At the 2nd, 4th, 6th and 8th week of the treatment, 24-hoururine was collected. Results: Table 1 summarizes the results. Urinarytotal protein and albumin began to markedly increase in vehicle-treatedrats two weeks after surgery. Whereas, in rats treated with compound 1,these parameters did not increase and each parameter was rathersignificantly low six to eight weeks after the beginning ofadministration as compared with vehicle-treated rats. Since compound 1suppresses aggravation of renal impairment, its efficacy inglomerulonephritis or diabetic nephropathy is expected.

TABLE 1 Antiproteinuric Action in subtotally (5/6) nephrectomized Rats 2weeks 4 weeks 6 weeks Preadminis- after the after the after the 8 weeksafter tration first dose first dose first dose the first dose UrinaryVehicle 33.1 ± 3.1 36.4 ± 5.2 39.4 ± 4.8 35.3 ± 6.1 55.1 ± 9.1 total (n= 8-9) protein Com- 32.8 ± 5.4 30.9 ± 5.2 27.7 ± 4.0 17.6 ± 5.6* 24.4 ±2.7** (mg/100 g/ pound 1 24 hr) (n = 9) Shams  9.7 ± 0.7 14.9 ± 1.5 13.1± 1.4 8.3 ± 0.5 11.9 ± 1.3 (n = 6) Urinary Vehicle  7.7 ± 2.6 12.0 ± 3.114.1 ± 3.0 15.1 ± 3.7 24.5 ± 7.1 albumin (n = 8-9) (mg/100 g/ Com-  7.3± 2.3  6.3 ± 2.9  6.8 ± 3.4*  7.4 ± 4.0*  5.6 ± 2.7** 24 hr) pound 1 (n= 9) Shams  2.1 ± 0.2  1.9 ± 0.2  2.1 ± 0.2  1.3 ± 0.2  1.6 ± 0.2 (n =6) Values are expressed as mean ± standard error. Significancedifference testing between controls and compound-1-treated rats orshams: *P < 0.05 **P < 0.01

Test Example 2

Antiproteinuric action in rats with non-insulin-dependent (NIDD)diabetes (Wistar fatty rats) (Ikeda, H., Shino, A., Matsuo, T.,Iwatsuka, H., and Suzuoki, Z.: Diabetes, 30, 1045 (1981) or Kava, R. A.,West, D. B., Lukasik, V. A., and Greenwood, M. R. C: Diabetes, 38,159(1989) Compound 1: (±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylateMethod: On the basis of blood glucose level and urinary protein content,11-week-old Wistar fatty rats were divided into two groups(vehicle-treated rats and rats treated with 1 mg/kg/day, p.o. ofcompound 1). Non-diabetic control rats (lean rats) were also used.Compound 1 was suspended in gum-arabic and the suspension was orallyadministered once a day for ten weeks. At the 2nd, 4th, 6th, 8th and10th week of the treatment, 24 hour urine was collected. The urine wascentrifuged at 3,000 rpm and a portion of the supernatant was desaltedon a column (Pharmacia PD10). Urinary total protein content and albumincontent were determined by Lowry and ELISA methods, respectively.Results: Table 2 summarizes the results. Urinary total protein contentincreased in vehicle-treated rats to about three times of the value inlean rats. This increase, however, was reduced to 1.2-1.5 times bythe-treatment with compound 1. Urinary albumin content also increased invehicle-treated rats to about 100 times of the value in lean rats. Thisincrease, however, was reduced to 20-30 times by the treatment withcompound 1. Compound 1 did not affect blood glucose level. Innon-insulin-dependent diabetic models, compound 1 is expected to beeffective against diabetic nephropathy by decreasing the urinary proteinwithout affecting the blood glucose level.

TABLE 2 Antiproteinuric Action in Rats with non-insulin-dependentdiabetes age 11 weeks 13 weeks 15 weeks 17 weeks 19 weeks 21 weeksUrinary vehicle 101 ± 5 94 ± 14 118 ± 16 135 ± 15 117 ± 15 143 ± 22total (n = 6) protein Com- 101 ± 6 69 ± 11 91 ± 12 97 ± 11* 79 ± 10* 74± 13* (mg/24 hr) pound 1 (n = 6) Lean 55 ± 2 36 ± 3 51 ± 3 51 ± 3 45 ± 245 ± 2 (n = 6) Urinary vehicle 2.9 ± 0.41 24.6 ± 7.5 42.7 ± 9.0 46.4 ±10.4 38.6 ± 6.4 28.6 ± 5.2 albumin (n = 6) (mg/24 hr) Com- 6.5 ± 0.411.2 ± 3.9 14.8 ± 6.1* 21.8 ± 8.2 10.7 ± 3.9* 15.4 ± 3.7* pound 1 (n =6) Lean 0.4 ± 0.02 0.4 ± 0.04 0.6 ± 0.05 0.7 ± 0.08 0.6 ± 0.04 0.4 ±0.03 (n = 6) Values are expressed as mean ± standard error. Figures inparentheses denote the number of rats. Significance difference testingbetween controls and compound-1-treated rats or lean rats: *P < 0.05.

Test Example 3

Acute Toxicity Test Compound 1: (±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylateThe LD₅₀ of compound 1 is 2,000 mg/kg or more for 4-week-old Jcl:ICRmice (males and females) and for 5-week-old Jcl:Wister rats (males andfemales) via single oral administration.

What is claimed is:
 1. A method for lowering urinary total protein orurinary albumin in a mammal comprising the step of administering apharmaceutically effective amount of a compound or salt thereofrepresented by formula:

wherein R¹ stands for H or a lower (C₁-C₄) alkyl; R² stands for a grouprepresented by the formula —CO—D″ where D″ stands for hydroxy or a lower(C₁-C₄) alkoxy group, the alkyl moiety of which optionally issubstituted with hydroxy, amino, halogen, lower (C₂-C₆) alkanoyloxy,lower (C₄-C₇) cycloalkanoyloxy, lower (C₁-C₆) alkoxycarbonyloxy, lower(C₃-C₇) cycloalkoxycarbonyloxy or lower (C₁-C₄) alkoxy; R³ stands for atetrazolyl, carboxyl group or a group represented by the formula

where i stands for —O— or 'S— and j stands for >C═O, >C═S or >S(O)_(m)where m is 0, 1 or 2; n stands for 1 or 2; ring A stands for a benzenering; Y stands for O, N(H) or S, to a mammal in need thereof.
 2. Themethod of claim 1, wherein R¹ stands for ethyl.
 3. The method of claim1, wherein R¹ stands for ethyl and Y stands for —O—.
 4. The method ofclaim 1, wherein R² stands for a lower alkoxycarbonyl group substitutedwith cyclohexyloxycarbonyloxy.
 5. The method of claim 1, wherein R³stands for one of the following:


6. The method of claim 1, wherein R³ stands for tetrazolyl.
 7. Themethod of claim 1, wherein R² stands for a lower alkoxycarbonyl groupsubstituted with a cyclohexyloxycarbonyloxy group and R³ stands for atetrazolyl group.
 8. The method of claim 1, wherein R¹ stands for alower alkyl group; Y stands for —O—; R² stands for a loweralkoxycarbonyl group substituted with a cyclohexyloxyvcarbonyloxy group;and R³ stands for a tetrazolyl group.
 9. The method of claim 1, whereinsaid compound represented by formula (I) is(±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate.10. The method of claim 1, wherein said compound represented by formula(I) is2-ethoxy-1-[[2′-(1H-tetrazl-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylicacid.
 11. The method of claim 1, wherein said compound represented byformula (I) is pivaloyloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate.12. The method of claim 1, wherein said compound represented by formula(I) is2-ethoxy-1-[[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazdle-7-carboxylicacid.
 13. The method of claim 1, wherein R² stands for a carboxyl group.14. The method of claim 1, wherein R³ stands for4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl.
 15. The method of claim 1,wherein the method is a method of treatment.